Aplicação à posologia dos antibióticos

O conhecimento dos diferentes parâmetros PK, em particular a biodisponibilidade, o Vd, a Cl, a T1/2, a AUC, tem implicações na prática clínica, sendo importantes para

Estes conceitos são particularmente úteis na presença de:

- Capacidade de realizar TDM na prática clínica, nomeadamente disponibilidade de testes laboratoriais rápidos, fiáveis e baratos;

- Relação conhecida entre a concentração do fármaco e o seu efeito clínico, quer terapêutico quer tóxico;

- Conhecimento da PK do fármaco in vivo e das principais alterações que decorrem da doença aguda.

- Conhecimento das principais interações medicamentosas.

A TDM de antibióticos foi inicialmente introduzida para prevenir a toxicidade de fármacos como os aminoglicosídeos e a vancomicina, os quais estavam associados a nefrotoxicidade quando a sua concentração de vale é demasiado elevada. Posteriormente, os estudos de PK permitiram avaliar a relação entre as suas concentrações séricas e a eficácia. Tal permitiu optimizar a posologia com recurso a equações de PK relativamente simples, o que se revelou particularmente útil para fazer face ao aumento das resistências bacterianas.

A optimização da posologia de outras classes antibióticas, igualmente guiadas por TDM, poderá também contribuir para preservar a sua eficácia e aumentar a segurança do doente. Está em desenvolvimento crescente a tecnologia que permitirá passar a TDM da investigação para a prática clínica. Essa estratégia permitirá ainda perceber melhor qual a concentração ideal de cada fármaco para obter a eficácia antibiótica desejada.

Todos estes aspectos foram abordados num artigo de revisão que escrevi a convite do editor da revista ICU Management, Prof. J. L. Vincent, para a edição de Outono de 2011 (artigo 2).

João Gonçalves Pereira, Pedro Póvoa. Impact of Pharmacokinetics of Antibiotics in ICU clinical practice. ICU Management 2011, 11:30-33

No mesmo descrevi os conceitos da PK, as suas alterações mais comuns no doente crítico, bem como as estratégias que podem ser usadas para as prever e para optimizar a posologia antibiótica, em relação com as suas características PD. No editorial da

mesma revista o Prof. J. L. Vincent referiu-se a este artigo “If you are hoping to bone up on or perhaps simply re-acquaint yourself with antibiotic pharmacokinetics, Drs. Pereira and Povoa provide a masterclass on the topic, flush with advice on whether we can use pharmacokinetics to guide antibiotic therapy”.

Bibliografia

1. Estes L. Review of pharmacokinetics and pharmacodynamics of antimicrobial

agents. Mayo Clin Proc 1998;73:1114–22.

2. Bauer, L. Applied Clinical Pharmacokinetics, 2nd ed. 2008 The McGraw-Hill

Companies

3. Mann HJ, Wittbrodt ET, Baghaie a a, Cerra FB. Effect of pharmacokinetic sampling methods on aminoglycoside dosing in critically ill surgery patients. Pharmacotherapy 18:371–8.

4. Roberts JA, Lipman J. Antibacterial dosing in intensive care:

pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet 2006;45:755–73.

5. Hilmer SN, Tran K, Rubie P, et al. Gentamicin pharmacokinetics in old age and frailty. Br J Clin Pharmacol 2011;71:224–31.

6. Li C, Kuti JL, Nightingale CH, Mansfield DL, Dana A, Nicolau DP.

Population pharmacokinetics and pharmacodynamics of

piperacillin/tazobactam in patients with complicated intra-abdominal infection. J Antimicrob Chemother 2005;56:388-395.

7. Beckwith MC, Feddema SS, Barton RG, Graves C. A Guide to Drug Therapy

in Patients with Enteral Feeding Tubes: Dosage Form Selection and Administration Methods. Hosp Pharm 2004;39:225–37.

8. Gorzoni ML, Della Torre A, Pires SL. Medicamentos e sondas de nutrição. Rev Assoc Med Bras 2010;56:17–21.

9. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before

initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006;34:1589–96.

10. Frame WT, Allison RH, Moir DD, Nimmo WS. Effect of naloxone on gastric

11. Crome P, Rizeq M, George S, Braithwaith RA, Jones PW. Drug absorption may be delayed after stroke: Results of the paracetamol absorption test. Age Ageing 2001;30:391–3.

12. Brundage, R. and Mann, H. General Principles of Pharmacokinetics and Pharmacodynamics. In: Fink, M., Abraham, E., Vincent, J., and Kochanek, P., (eds), Textbook of Critical Care. 2005 Elsevier: Philadelphia.

13. De Paepe P, Belpaire FM, Buylaert WA. Pharmacokinetic and

pharmacodynamic considerations when treating patients with sepsis and septic shock. Clin Pharmacokinet 2002;41:1135–51.

14. Power BM, Forbes AM, van Heerden P V, Ilett KF. Pharmacokinetics of drugs

used in critically ill adults. Clin Pharmacokinet 1998;34:25–56.

15. Fry DE. The importance of antibiotic pharmacokinetics in critical illness. In: Am J Surg. 1996; 172: 20S-25S.

16. Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic

considerations in patients with liver disease. An update. Clin Pharmacokinet 1995;29:370–91.

17. Liu P, Derendorf H. Antimicrobial tissue concentrations. Infect Dis Clin North Am. 2003;17:599–613.

18. Benet LZ, Hoener B. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002;71:115–21.

19. Ulldemolins M, Roberts JA, Wallis SC, Rello J, Lipman J. Flucloxacillin dosing in critically ill patients with hypoalbuminaemia: Special emphasis on unbound pharmacokinetics. J Antimicrob Chemother 2010;65:1771–8.

20. Dahyot C, Marchand S, Bodin M, Debeane B, Mimoz O, Couet W. Application

of basic pharmacokinetic concepts to analysis of microdialysis data: Illustration with imipenem muscle distribution. Clin Pharmacokinet 2008;47:181–9. 21. Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Piperacillin

penetration into tissue of critically ill patients with sepsis--bolus versus continuous administration? Crit Care Med 2009;37:926–33.

22. Thallinger C, Buerger C, Plock N, et al. Effect of severity of sepsis on tissue concentrations of linezolid. J Antimicrob Chemother 2008;61:173–6.

23. Wong G, Sime F, Lipman J, Roberts J a. How do we use therapeutic drug monitoring to improve outcomes from severe infections in critically ill patients? BMC Infect Dis 2014;14:288.

Artigo  2

The efficacy of a drug is mainly dependent on its ability to achieve an effective concentration in the target tissue. However the risk of toxicity limits the dose that can be administered.

Critically ill patients often have increased car- diac output, capillary leak, modification of pro- teins serum levels and binding properties. Additionally increased renal and hepatic clear- ance or, on the contrary, organ failure, are com- mon and lead to significant pharmacokinetic (PK) changes (Roberts and Lipman 2006). Antibiotic dosing is especially challenging in these patients, due to increased volume of dis- tribution (Vd) and changes in clearance (Cl). Besides antibiotics killing kinetics is dependent on drug class, and different patterns of expo- sure are necessary for antimicrobial success (Drusano 2004).

Unfortunately, therapeutic drug monitoring is only available for a small number of antibiotics. Nevertheless knowledge of PK may help to se- lect appropriate dosage and schedule intervals that might contribute to therapeutic success.

Principles of Pharmacokinetics

Pharmacokinetic refers to the study of drug con- centration during a timeframe and its distribu- tion in different tissues of the body, namely its absorption, bioavailability, distribution, protein binding, and also its metabolism and excretion. Clinical PK is the application of these principles to design individualised dosage regimens, which optimise therapeutic response while minimising the chance of an adverse drug reaction.

Bioavailability is the drug proportion, which actually reaches systemic circulation (usually 100% for intravenous route). Distribution oc- curs when drug molecules leave the vascular sys- tem to different compartments, either tissues or organs. Their chemical conversion is called me- tabolism. Excretion is the irreversible elimina- tion of a drug from the body.

Most drugs follow a linear PK (its concentra- tion changes proportionally with dose). However, some, like phenytoin, presents non linear, Michaelis-Menten, PK (Bauer 2008).

Pharmacodynamics (PD) relates drug concen- tration to the pharmacological response. However, drug effect may not be proportional to drug con- centration because the pharmacological drug ef- fect depends on its ability to form a complex with a receptor. Once these are saturated, a max- imum response will be obtained. Often adverse effects of drugs follow the same type of concen- tration response relationship.

Volume of Distribution

Serum concentration of a drug depends of the amount delivered, its bioavailability and the Vd. The Vd is a mathematical construct and refers to the size of a compartment necessary to account for the total amount of the drug, assuming that its concentration in the whole body is the same as the measured in plasma [Vd=(dose*bioavail- ability)/concentration]. Drugs that distribute mainly in the extracellular fluid have low Vd (0.2- 0.3L/kg), whilst drugs that have rapid cellular uptake have high Vd (in excess of 0.6 L/Kg).

In general, Vd is above normal in critically ill patients. Volume resuscitation, blood products, vasopressors, positive pressure ventilation, sur- gical procedures, capillary leak and reduction in albumin serum concentration, all contribute to this increase in Vd. Therefore with the same dose, peak concentrations are usually lower. This is es- pecially important after the first dose of a drug, when the drug concentration is only dependent on the Vd. If a lower dose is given (namely to ad- just for renal failure), a lower concentration will be obtained, which may contribute to therapeu- tic failure. Nevertheless maintenance doses should be reduced (or intervals enlarged) to avoid ac- cumulation and toxicity.

When drug Cl remains unchanged, a rise in Vd, although associated with a lower concentra- tion, proportionally increases the t1/2, since João Gonçalves-Pereira, MD EdankVaZci>ciZch^kZ8VgZJc^i Hd;gVcX^hXdMVk^Zg=dhe^iVa 8Zcigd=dhe^iVaVgA^hWdV DX^YZciVa A^hWdc!Edgij\Va joaogpster@gmail.com